DE69631774T2 - 2,3-DIOXO-1,2,3,4-TETRAHYDRO-CHINOXALINE DERIVATIVES - Google Patents
2,3-DIOXO-1,2,3,4-TETRAHYDRO-CHINOXALINE DERIVATIVES Download PDFInfo
- Publication number
- DE69631774T2 DE69631774T2 DE69631774T DE69631774T DE69631774T2 DE 69631774 T2 DE69631774 T2 DE 69631774T2 DE 69631774 T DE69631774 T DE 69631774T DE 69631774 T DE69631774 T DE 69631774T DE 69631774 T2 DE69631774 T2 DE 69631774T2
- Authority
- DE
- Germany
- Prior art keywords
- dioxo
- tetrahydroquinoxalin
- nitro
- ylmethyl
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- ABJFBJGGLJVMAQ-UHFFFAOYSA-N 1,4-dihydroquinoxaline-2,3-dione Chemical class C1=CC=C2NC(=O)C(=O)NC2=C1 ABJFBJGGLJVMAQ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 22
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000004471 Glycine Substances 0.000 claims description 4
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims description 4
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims description 4
- 102000003678 AMPA Receptors Human genes 0.000 claims description 3
- 108090000078 AMPA Receptors Proteins 0.000 claims description 3
- 102000000079 Kainic Acid Receptors Human genes 0.000 claims description 3
- 108010069902 Kainic Acid Receptors Proteins 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- VGCLKYODUBTNNY-UHFFFAOYSA-N 1-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]ethylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CNC(C)P(O)(O)=O VGCLKYODUBTNNY-UHFFFAOYSA-N 0.000 claims description 2
- CVVQUZACMDLTGQ-UHFFFAOYSA-N 2-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]ethylphosphonic acid Chemical compound [O-][N+](=O)C1=CC(CNCCP(O)(O)=O)=C2N=C(O)C(O)=NC2=C1 CVVQUZACMDLTGQ-UHFFFAOYSA-N 0.000 claims description 2
- KYLYSVRHMNUBIV-UHFFFAOYSA-N 3-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]propylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CNCCCP(O)(=O)O KYLYSVRHMNUBIV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 2
- KVWLBFCBESPEBG-UHFFFAOYSA-N 4-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]-2-phosphonobutanoic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CNCCC(C(=O)O)P(O)(O)=O KVWLBFCBESPEBG-UHFFFAOYSA-N 0.000 claims description 2
- GUOSQOGZNURVEG-UHFFFAOYSA-N 4-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]butylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CNCCCCP(O)(=O)O GUOSQOGZNURVEG-UHFFFAOYSA-N 0.000 claims description 2
- UUVJYYBXBRFJPI-UHFFFAOYSA-N 4-[methyl-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl]amino]butylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CN(CCCCP(O)(O)=O)C UUVJYYBXBRFJPI-UHFFFAOYSA-N 0.000 claims description 2
- BCGHZAALMKKRSG-VXNVDRBHSA-N [(1r,2r)-2-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]cyclopropyl]phosphonic acid Chemical compound OP(O)(=O)[C@@H]1C[C@H]1NCC1=CC([N+]([O-])=O)=CC2=C1NC(=O)C(=O)N2 BCGHZAALMKKRSG-VXNVDRBHSA-N 0.000 claims description 2
- QEBUJTHSVVYHNO-UHFFFAOYSA-N [(3-methoxyphenyl)-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]methyl]phosphonic acid Chemical compound COC1=CC=CC(C(NCC=2C=3NC(=O)C(=O)NC=3C=C(C=2)[N+]([O-])=O)P(O)(O)=O)=C1 QEBUJTHSVVYHNO-UHFFFAOYSA-N 0.000 claims description 2
- CSUJCEIZXZMTAW-UHFFFAOYSA-N [(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl-(2-phenylacetyl)amino]methylphosphonic acid Chemical compound C=1C(Br)=CC=2NC(=O)C(=O)NC=2C=1CN(CP(O)(=O)O)C(=O)CC1=CC=CC=C1 CSUJCEIZXZMTAW-UHFFFAOYSA-N 0.000 claims description 2
- BJUHRYJWPVCZLX-UHFFFAOYSA-N [(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methyl-phenylmethoxycarbonylamino]methylphosphonic acid Chemical compound C=1C(Br)=CC=2NC(=O)C(=O)NC=2C=1CN(CP(O)(=O)O)C(=O)OCC1=CC=CC=C1 BJUHRYJWPVCZLX-UHFFFAOYSA-N 0.000 claims description 2
- NWCJKAPQZJBNQG-UHFFFAOYSA-N [2-[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)amino]-2-oxoethyl]phosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2NC(=O)CP(O)(=O)O NWCJKAPQZJBNQG-UHFFFAOYSA-N 0.000 claims description 2
- ABFMMCZFKUIJGQ-UHFFFAOYSA-N becampanel Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C=C2CNCP(O)(=O)O ABFMMCZFKUIJGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- GATNOFPXSDHULC-UHFFFAOYSA-N ethylphosphonic acid Chemical compound CCP(O)(O)=O GATNOFPXSDHULC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- LBJPOQXTEVGSFL-UHFFFAOYSA-N [[(7-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]-pyridin-3-ylmethyl]phosphonic acid Chemical compound C=1C([N+]([O-])=O)=CC=2NC(=O)C(=O)NC=2C=1CNC(P(O)(=O)O)C1=CC=CN=C1 LBJPOQXTEVGSFL-UHFFFAOYSA-N 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- -1 2,3-dioxo-1,2,3,4-tetrahydroquinoxalinyl Chemical class 0.000 description 25
- 235000002639 sodium chloride Nutrition 0.000 description 22
- 239000000243 solution Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000008273 gelatin Substances 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 229940014259 gelatin Drugs 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 235000011852 gelatine desserts Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 150000003973 alkyl amines Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229940097362 cyclodextrins Drugs 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 239000000463 material Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 3
- 235000015424 sodium Nutrition 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
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- 230000001225 therapeutic effect Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- DBXRCHXKTJHESM-UHFFFAOYSA-N 2,3-dimethoxy-5-[(2-methylaziridin-1-yl)methyl]-7-nitroquinoxaline Chemical compound C=12N=C(OC)C(OC)=NC2=CC([N+]([O-])=O)=CC=1CN1CC1C DBXRCHXKTJHESM-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BGKFPRIGXAVYNX-UHFFFAOYSA-N 5,7-dichloro-4-oxo-1H-quinoline-2-carboxylic acid Chemical compound ClC1=CC(Cl)=CC2=NC(C(=O)O)=CC(O)=C21 BGKFPRIGXAVYNX-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- NVQLTEKPZZTDBI-UHFFFAOYSA-N [(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylamino]methylphosphonic acid Chemical compound BrC1=CC(CNCP(O)(O)=O)=C2N=C(O)C(O)=NC2=C1 NVQLTEKPZZTDBI-UHFFFAOYSA-N 0.000 description 2
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- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical class C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 description 2
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- NPYSGAQZDKLFNW-UHFFFAOYSA-N (2,3-dimethoxy-7-nitroquinoxalin-5-yl)methanamine Chemical compound [O-][N+](=O)C1=CC(CN)=C2N=C(OC)C(OC)=NC2=C1 NPYSGAQZDKLFNW-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
- C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems
Description
Die Erfindung bezieht sich auf 2,3-Dioxo-1,2,3,4-tetrahydrochinoxalinylderivate, ausgewählt ausThe Invention relates to 2,3-dioxo-1,2,3,4-tetrahydroquinoxalinyl derivatives, selected out
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-2-aminoethan-phosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -2-aminoethane-phosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)aminomethanphosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) aminomethanephosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)amino-(3-methoxyphenyl)methanphosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino (3-methoxyphenyl) methanephosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-3-aminopropan-1-phosphonsäure; trans-2-[N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)amino]cyclopropan-1-phosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -3-aminopropane-1-phosphonic acid; trans-2- [N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino] cyclopropane-1-phosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)amino-(3-pyridyl)methanphosphonsäwe; N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-3-amino-l-carboxypropan-1-phosphonsäure; 1-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethylamino)ethanphosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino (3-pyridyl) methanphosphonsäwe; N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -3-amino-l-carboxypropane-1-phosphonic acid; 1- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethylamino) ethanephosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yl)-carbamoyhnethanphosphonsäwe; 7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethylaminomethanphosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) -carbamoyhnethanphosphonsäwe; 7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethylaminomethanphosphonsäure;
- 1-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethylamino)ethanphosphonsäure;1- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethylamino) ethanephosphonic acid;
- N-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-N-benzyloxycarbonylaminomethanphosphonsäure;N- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -N-benzyloxycarbonylaminomethanphosphonsäure;
- N-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-N-phenylacetylaminomethanphosphonsäwe;N- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -N-phenylacetylaminomethanphosphonsäwe;
- [(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yl-methylamino)-(3-hydroxyphenyl)methyl]phosphonsäwehydrobromid;[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl-methylamino) - (3-hydroxyphenyl) methyl] phosphonsäwehydrobromid;
- N-(2,3-Dioxo-7-nitro- 1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-4-amino-n-butylphosphonsäure;N- (2,3-dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -4-amino-n-butylphosphonic acid;
- N-(2,3-Dioxo-7-nitro- 1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-N-methyl-4-amino-n-butylphosphonsäwe (im Folgenden kollektiv als die Verbindungen bezeichnet) und die Salze hiervon.N- (2,3-dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -N-methyl-4-amino-n-butylphosphonic acid (hereinafter collectively referred to as the compounds) and the salts thereof.
Strukturell verwandte Chinoxalindione, die antikonvulsive Eigenschaften aufweisen, sind aus WO 95 12 417 A, WO 96 08 485 A und WO 96 09 295 A bekannt. Diese Verbindungen sind jedoch vorwiegend wegen ihrer Löslichkeitsprobleme nie als Pharmazeutika entwickelt worden. Die fehlende Flüssigkeit der Chinoxalindione ist als Hindernis für deren therapeutische Anwendung verbreitet anerkannt, siehe beispielsweise Xue D et al, J Cerebral blood flow and metabolism 1994, 14: 251 bis 261).Structurally related quinoxalinediones which have anticonvulsant properties, are known from WO 95 12 417 A, WO 96 08 485 A and WO 96 09 295 A. However, these compounds are predominantly because of their solubility problems never been developed as pharmaceuticals. The missing fluid The quinoxalindione is an obstacle to their therapeutic use commonly recognized, see, for example, Xue D et al, J Cerebral blood flow and metabolism 1994, 14: 251-261).
Es wurde nun überraschenderweise erkannt, dass diese Verbindungen über eine Wasserlöslichkeit verfügen, die mit ihrer Entwicklung als Arzneimittel kompatibel ist, während sie zugleich gute antikonvusive Eigenschaften aufweisen.It was now surprisingly recognized that these compounds have a water solubility, the is compatible with their development as a drug while they have at the same time good anticonvusive properties.
Die Verbindungen können Salze mit Basen, Säweadditionssalze und innere Salze bilden.The Connections can Salts with bases, Säweadditionssalze and form internal salts.
Salze der Verbindungen mit Basen sind beispielsweise solche mit pharmazeutisch annehmbaren Basen, wie nicht toxische Metallsalze, die abgeleitet sind von Metallen der Gruppen Ia, Ib, IIa und IIb, beispielsweise Alkalimetallsalze, insbesondere Natrium- oder Kaliumsalze, Erdalkalimetallsalze, insbesondere Calcium- oder Magnesiumsalze, und auch Ammoniumsalze mit Ammoniak oder organischen Aminen oder quaternären Ammoniumbasen, wie optional C-hydroxylierte aliphatische Amine, insbesondere Mono-, Di- oder Triniederalkylamine, beispielsweise Methyl-, Ethyl- oder Diethylamin, Mono-, Di- oder Tri-(hydroxylniederalkyl)amine, wie Ethanolamin, Diethanolamin oder Triethanolamin, Tris(hydroxymethyl)methylamin oder 2-Hydroxy-tert-butylamin oder N-(Hydroxyniederalkyl)-N,N-diniederalkyl)-N,N-diniederalkylamine oder N-(Polyhydroxyniederalkyl)-N-niederalkylamine, wie 2-(Dimethylamin)ethanol oder D-Glucamin oder Cholin oder quaternäre aliphatische Ammoniumhydroxide, beispielsweise Tetrabutylammoniumhydroxid.salts the compounds with bases are, for example, those with pharmaceutical acceptable bases, such as non-toxic metal salts derived are of metals of groups Ia, Ib, IIa and IIb, for example Alkali metal salts, in particular sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases, as optional C-hydroxylated aliphatic amines, in particular mono-, Di- or tri-lower alkylamines, for example methyl, ethyl or Diethylamine, mono-, di- or tri- (hydroxyl-lower alkyl) amines, such as Ethanolamine, diethanolamine or triethanolamine, tris (hydroxymethyl) methylamine or 2-hydroxy-tert-butylamine or N- (hydroxy-lower alkyl) -N, N-lower-alkyl) -N, N-lower alkylamines or N- (polyhydroxy-lower alkyl) -N-lower alkylamines, such as 2- (dimethylamine) ethanol or D-glucamine or choline or quaternary aliphatic ammonium hydroxides, for example, tetrabutylammonium hydroxide.
Säweadditionssalze der Verbindungen sind beispielsweise die pharmazeutisch annehmbaren Salze hiervon mit geeigneten Mineralsäwen, wie Halogenwasserstoffsäwen, Schwefelsäwe oder Phosphonsäure, beispielsweise Hydrochloride, Hydrobromide, Sulfate, Hydrogensulfates oder Phosphate, Salze mir geeigneten Carbonsäwen, wie optional hydroxylierten Niederalkansäwen, beispielsweise Essigsäwe, Glycolsäwe, Propionsäwe, Milchsäure oder Pivalinsäure, mit optional hydroxylierten und/oder oxosubstituierten Niederalkandicarbonsäuren, beispielsweise Oxalsäwe, Bemsteinsäwe, Fumarsäure, Maleinsäwe, Weinsäwe, Citronensäure, Brenztraubensäure, Apfelsäure, Ascorbinsäwe, und auch mit aromatischen heteroaromatischen oder araliphatischen Carbonsäuren, wie Benzoesäwe, Nicotinsäwe oder Mandelsäure, und Salze mit geeigneten aliphatischen oder aromatischen Sulfonsäuren oder Nsubstituierten Sulfaminsäwen, wie Methansulfonate, Benzolsulfonate, p-Toluolsulfonate oder N-Cyclohexylsulfamate (Cyclamate).Säweadditionssalze The compounds are, for example, the pharmaceutically acceptable Salts thereof with suitable mineral acids, such as hydrogen halides, sulfuric acid or Phosphonic acid, for example Hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, Salts with suitable carbonates, such as optionally hydroxylated lower alkanes, for example acetic, glycolic, propionic, lactic or pivalic, with optionally hydroxylated and / or oxo-substituted lower alkanedicarboxylic acids, for example Oxalsäwe, Bemsteinsäwe, fumaric acid, Maleinsäwe, Weinsäwe, citric acid, Pyruvic acid, Malic acid, Ascorbinsäwe, and also with aromatic heteroaromatic or araliphatic Carboxylic acids, like benzoesäwe, Nicotinsäwe or mandelic acid, and salts with suitable aliphatic or aromatic sulfonic acids or N substituted sulfaminae, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamates (Cyclamates).
Ferner sind sowohl Total- als auch Partialsalze eingeschlossen, nämlich Salze mit 1, 2 oder 3, vorzugsweise mit 2, Äquivalenten einer Base pro mol an Säure einer Verbindung oder Salze mit 1, 2 oder 3 Äquivalenten, vorzugsweise 1 Äquivalent, einer Säwe pro mol Base einer Verbindung.Furthermore, both total and partial salts are included, namely salts with 1, 2 or 3, preferably with 2, equivalents of base per mole of acid of a compound or salts with 1, 2 or 3 equivalents, preferably 1 equivalent, of one acid per mole of base of a compound.
Zum Zwecke einer Isolierung und Reinigung können auch pharmazeutisch nicht annehmbare Salze verwendet werden. Therapeutisch werden aber nur die pharmazeutisch annehmbaren nicht toxischen Salze verwendet, die daher bevorzugt sind.To the Purposes of isolation and purification can not be pharmaceutically acceptable salts are used. Therapeutic but only uses the pharmaceutically acceptable non-toxic salts, which are therefore preferred.
Die Verbindungen verfügen über wertvolle pharmakologische Eigenschaften. Sie verfügen über ein hohes Ausmaß an Bindungsaffinität für AMPA-Rezeptoren, Kainatrezeptoren und/oder Glycinbindungsstellen von NMDA-Rezeptoren. Die Affinität für die erwähnten Rezeptoren ist entsprechend der Struktur global und selektiv. Die Verbindungen zeigen vor allem eine starke Affinität für AMPA- und/oder Kainatbindungsstellen und eine weniger starke Affinität für Glycinbindungsstellen des NMDA-Rezeptors.The Connections have valuable pharmacological properties. They have a high degree of binding affinity for AMPA receptors, Kainate receptors and / or glycine binding sites of NMDA receptors. The affinity for the mentioned receptors is global and selective according to the structure. The connections show above all a strong affinity for AMPA and / or Kainatbindungsstellen and a less strong affinity for glycine binding sites of the NMDA receptor.
Das Bindungsvermögen der Verbindungen und ihrer Salze kann in vitro radiographisch in Himmembranen von Ratten (Mäuse, Ratten) mit Bezug auf die Verschiebung von [3H]-AMPA, [3H]-Kainat oder DCKA (5,7-Dichlorkynurensäure), gemessen werden, wobei der für eine 50%ige Verschiebung (IC50-Wert) erforderliche Konzentration für mehrere Konzentrationen bestimmt wird.The binding capacity of the compounds and their salts can be measured in vitro radiographically in rat cyst membranes (mice, rats) with respect to the displacement of [ 3 H] -AMPA, [ 3 H] -cainate or DCKA (5,7-dichlorokynurenic acid) where the concentration required for a 50% shift (IC 50 value) is determined for multiple concentrations.
Zur Bestimmung der Bindungsaffinität für AMPA-Rezeptoren lässt sich beispielsweise der Radiorezeptorversuch von T. Honore, J. Lauridsen und Krogsgaard-Larsen verwenden, wie er in J Neurochem 38, 173 bis 178, beschneben wird, wobei die Verbindungen IC50-Werte von etwa 0,05 bis etwa 5 µM aufweisen. Die Bindungsaffinität für Kainatrezeptoren lässt sich beispielsweise messen durch den Radiorezeptorversuch von J.R. Simon, J.F.For example, to determine binding affinity for AMPA receptors, the radioreceptor assay of T. Honore, J. Lauridsen and Krogsgaard-Larsen, as will be described in J Neurochem 38, 173-178, may be used, the compounds having IC 50 values of approximately 0.05 to about 5 μM. The binding affinity for kainate receptors can be measured, for example, by the radioreceptor experiment of JR Simon, JF
Contrera und M.J. Kuhn, J Neurochem 26, 141 bis 147, wonach die Verbindungen IC50-Werte von etwa 0,5 bis etwa 5 µM zeigen.Contrera and MJ Kuhn, J Neurochem 26, 141-147, according to which the compounds show IC 50 values of about 0.5 to about 5 μM.
Das Bindungsvermögen der Verbindungen an Glycinbindungsstellen des NMDA-Rezeptors kann beispielsweise bestimmt werden im Radiorezeptorversuch nach M.B. Baron, B.W. Siegel et al, Eur J Pharmacol, Molec Pharmacol Section 206, Seiten 149 bis 154 (1991), und T. Canton, A. Dohle et al, 7 Phann Phannacol 44, Seiten 812 bis 816 (1992), an Rattencortex- und Rattenhippocampusmembranen. Bei diesem experimentellen Verfahren liegt der IC50-Wert der Verbindungen im Bereich von etwa 0,005 bis etwa 5 µM.The binding capacity of the compounds to glycine binding sites of the NMDA receptor can be determined, for example, in the radioreceptor experiment according to MB Baron, BW Siegel et al, Eur J Pharmacol, Molec Pharmacol Section 206, pages 149-154 (1991), and T. Canton, A. Dohle et al, 7 Phann Phannacol 44, pages 812 to 816 (1992) on rat cortex and rat hippocampal membranes. In this experimental procedure, the IC 50 value of the compounds ranges from about 0.005 to about 5 μM.
Infolge dieser Eigenschaften verfügen die Verbindungen über ausgeprägte antikonvulsive Eigenschaften, die sich in vivo beispielsweise an der Maus durch Bezug auf ihre ausgeprägte Schutzwirkung gegenüber Konvulsionen, die durch Elektroschock oder Metrazole ausgelöst werden, wozu beispielsweise Gebrauch gemacht werden kann vom gut etablierten Elektroschockmodell an der Maus oder dem Maulmodell für durch Metrazol induzierte Konvulsionen nach Schmutz et al, Naunyn-Schmiedebergs Arch Pharmacol 342, 61 bis 66 (1990).As a result have these properties the connections over pronounced anticonvulsant properties, for example, in vivo the mouse by reference to its pronounced protective effect against convulsions, which are triggered by electroshock or Metrazole, including, for example Use can be made of the well established electroshock model in the mouse or mouth model for metrazol induced Spatters according to Schmutz et al, Naunyn-Schmiedeberg's Arch Pharmacol 342, 61 to 66 (1990).
Die Verbindungen und die pharmazeutisch annehmbarn Salze hiervon sind daher hervorragend geeignet für die prophylaktische und therapeutische Behandlung von pathologischen Zuständen, die eine Reaktion darstellen auf eine Blockierung einer oder mehrerer der erwähnten Untertypen von exzitatorischen Aminosäwerezeptoren, beispielsweise newodegenerativen Störungen, wie sie herrühren von Schlaganfällen, Hypoglycaemie, Anoxie oder Symptomen für Zerebralparalyse; ischaemischen Hirnstörungen, wie Zerebralischaemie, Zerebralischaemie bei einer Herzoperation oder einem Herzstillstand, Perinatalasphyxie, epileptischen Anfällen, Huntington-Chorea, Alzheimer Krankheit und Parkinson-Krankheit, amyotrophischer Lateralsklerose, spinalem und zerebralem Trauma, und auch Vergiftungssymptomen infolge von Newotoxinen und Drogenmissbrauch, und ischaemischen Störungen der Augen, Vascular- und Muskelspasmen, wie Migräne oder lokaler oder allgemeiner Spastik, Konvulsionen, wie Epilepsie, sowie Angstzuständen und Schmerz, wie Trigeminusneuralgien.The Compounds and the pharmaceutically acceptable salts thereof therefore ideally suited for the prophylactic and therapeutic treatment of pathological states which represent a reaction to a blockage of one or more the mentioned Sub-types of excitatory amino acid receptors, for example new-degenerative disorders, how they come from from strokes, Hypoglycaemia, anoxia or symptoms of cerebral palsy; ischemic Brain disorders, like cerebral ischemia, cerebral ischemia in heart surgery or cardiac arrest, perinatal asphyxia, epileptic seizures, Huntington's chorea, Alzheimer's disease and Parkinson's disease, amyotrophic lateral sclerosis, spinal and cerebral trauma, and also intoxication symptoms as a result of Newotoxins and drug abuse, and ischemic disorders of the Eyes, vascular and muscle spasms, such as migraine or local or more common Spasticity, convulsions, such as epilepsy, as well as anxiety and Pain, like trigeminal neuralgia.
Das Verfahren zur Herstellung der Verbindungen wird in den Beispielen beschrieben.The Process for preparing the compounds is described in the examples described.
Die Erfindung bezieht sich auch auf pharmazeutische Zusammensetzungen, welche die Verbindungen oder pharmazeutisch annehmbare Salze hiervon als Wirkstoffenihalten.The Invention also relates to pharmaceutical compositions, which compounds or pharmaceutically acceptable salts thereof as active ingredients.
Die erfindungsgemäßen pharmazeutischen Zusammensetzungen, welche die erfindungsgemäßen Verbindungen oder pharmazeutisch annehmbaren Salze hiervon enthalten, sind geeignet für eine enterale, wie orale und auch rektale, und eine parenterale Verabreichung an Warmblüter, wobei die Zusammensetzungen den phannakologischen Wirkstoff allein oder zusammen mit einem pharmazeutisch annehmbaren Träger enthalten. Die Tagesdosis des Wirkstoffs ist abhängig vom Alter und individuellem Zustand und von der Art der Verabreichung.The pharmaceutical compositions of the present invention containing the compounds of the present invention or pharmaceutically acceptable salts thereof are suitable for enteral, such as oral, rectal, and parenteral administration to warm-blooded animals contain the pharmacological agent alone or together with a pharmaceutically acceptable carrier. The daily dose of the active substance depends on the age and individual condition and on the mode of administration.
Die neuen pharmazeutischen Zusammensetzungen enthalten beispielsweise etwa 10% bis etwa 80%, vorzugsweise etwa 20% bis etwa 60%, Wirkstoff Die erfindungsgemäßen pharmazeutischen Zusammensetzungen zur enterallen oder parenteralen Verabreichung sind beispielsweise Einheitsdosierungsformen, wie Dragees, Tabletten, Kapseln oder Suppositorien und auch Ampullen. Sie werden in an sich bekannter Weise hergestellt, beispielsweise durch herkömmliche Misch-, Granulier-, Konfektionier-, Löse- oder Lyophilisierverfahren. Pharmazeutische Zusammensetzungen zur oralen Verabreichung lassen sich beispielsweise erhalten durch Kombination des Wirkstoffs mit festen Trägern, optionale Granulierung des erhaltenen Gemisches und Verarbeitung des Gemisches oder der Granulate, falls gewünscht oder erforderlich, nach der Zugabe geeigneter Hilfsstoffe unter Bildung von Tabletten oder Drageekernen.The For example, new pharmaceutical compositions contain from about 10% to about 80%, preferably from about 20% to about 60%, active ingredient The pharmaceutical according to the invention Compositions for enteric or parenteral administration are, for example, unit dosage forms such as dragees, tablets, Capsules or suppositories and also ampoules. They are in themselves made known manner, for example by conventional Mixing, granulating, compounding, dissolving or lyophilization process. Allow pharmaceutical compositions for oral administration For example, obtained by combining the drug with solid straps, optional granulation of the resulting mixture and processing of the mixture or granules, if desired or required the addition of suitable excipients to form tablets or Tablet cores.
Geeignete Träger sind insbesondere Füllstoffe, wie Zucker, beispielsweise Lactose, Saccharose, Mannit oder Sorbit, Cellulosezubereitungen und/oder Calciumphosphate, beispielsweise Tricalciumphosphat oder Calciumhydrogenphosphat, und auch Bindemittel, wie Stärkepasten auf Basis von beispielsweise Mais-, Weizen-, Reis- oder Kartoffelstärke, Gelatine, Tragacanth, Methylcellulose und/oder Polyvinylpyrrolidon, gewünschtenfalls Zerfallhilfsmittel, wie die oben erwähnten Stärken und auch Carboxymethylstärke, quervernetztes Polyvinylpynolidon, Agar, Alginsäure oder ein Salz hiervon, wie Natriumalginat. Hilfsstoffe sind insbesondere Fließmittel, Fließkonditionierer und Gleitmittel, beispielsweise Kieselsäure, Talcum, Stearinsäure oder Salze hiervon, wie Magnesium- oder Calciumstearat, und/oder Polyethylenglycol. Drageekerne sind mit geeigneten, optional entertschen, Überzügen versehen, wozu unter anderem konzentrierte Zuckerlösungen verwendet werden, die Gummi arabicum, Talcum, Polyvinylpynolidon, Polyethylenglycol und/oder Titandioxid enthalten können, oder es werden hierzu auch Beschichtungslösungen in geeigneten organischen Lösemitteln oder Lösemittelgemischen oder zur Herstellung enterischer Überzüge auch Lösungen in geeigneten Cellulosepräparationen verwendet, wie Acetylcellulosephthalat oder Hydroxypropylcellulosephthalat. Den Beschichtungen für die Tabletten oder Dragees können auch Farbstoffe oder Pigmente zugesetzt werden, die beispielsweise zu Identifizierungszwecken oder zur Kennzeichnung unterschiedlicher Wirkstoffdosen dienen.suitable carrier are in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, Cellulose preparations and / or calcium phosphates, for example Tricalcium phosphate or calcium hydrogen phosphate, and also binders, like starch pastes based on, for example, corn, wheat, rice or potato starch, gelatin, Tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired Disintegrants, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked Polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are in particular Flow agents, flow conditioners and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, optional entertschen, coatings, which uses concentrated sugar solutions, among others Gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and / or May contain titanium dioxide, or it also coating solutions in suitable organic solvents or solvent mixtures or for the preparation of enteric coatings also solutions in suitable cellulose preparations used, such as acetyl cellulose phthalate or hydroxypropyl cellulose phthalate. The coatings for the tablets or dragees can It is also possible to add dyes or pigments which, for example, too For identification purposes or to identify different Serve active ingredient doses.
Andere oral verabreichbare pharmazeutische Zusammensetzungen sind Hartgelatinekapseln und auch weiche versiegelte Kapseln, die aus Gelatine und einem Weichmacher bestehen, wie Glycerin oder Sorbit. Die Hartgelatinekapseln können den Wirkstoff in Form von Granulaten enthalten, und zwar beispielsweise im Gemisch mit Füllstoffen, wie Lactose, Bindermtteln, wie Stärken, und/oder Gleitmitteln, wie Talcum oder Magnesiumstearat, und gewünschtenfalls mit Stabilisatoren. In Weichkapseln ist der Wirkstoff vorzugsweise in geeigneten Flüssigkeiten gelöst oder suspendiert, wie Fettölen, Paraffinöl oder flüssigen Polyethylenglycolen, wobei fallweise auch Stabilisatoren zugesetzt werden können.Other Orally administrable pharmaceutical compositions are hard gelatin capsules and also soft sealed capsules made of gelatin and a Plasticizers exist, such as glycerol or sorbitol. The hard gelatin capsules can contain the active ingredient in the form of granules, for example in Mixture with fillers, such as lactose, binder, such as starches, and / or lubricants, such as talc or magnesium stearate, and if desired with stabilizers. In soft capsules, the active ingredient is preferably in suitable liquids solved or suspended, such as fatty oils, paraffin oil or liquid Polyethylene glycols, with occasionally added stabilizers can be.
Geeignete rektal verabreichbare pharmazeutische Zusammensetzungen sind beispielsweise Suppositorien, die aus einer Kombination des Wirkstoffs mit einer Suppositoriengrundlage bestehen. Materialien für geeignete Suppositoriengrundlagen sind beispielsweise natürliche oder synthetische Triglyceride, Paraffinkohlenwasserstoffe, Polyethylenglycole und höhere Alkohole. Es lassen sich auch Gelatinetalcumapseln verwenden, die eine Kombination des Wirkstoffs mit einem geeigneten Grundlagenmaterial enthalten. Geeignete Grundlagenmaterialien sind beispielsweise flüssige Triglyceride, Polyethylenglycole oder Paraffinkohlenwasserstoffe.suitable For example, rectally administrable pharmaceutical compositions Suppositories consisting of a combination of the active ingredient with a Suppository basis exist. Materials for appropriate suppository bases are natural, for example or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols and higher Alcohols. It is also possible Gelatinetalcumapseln use the a combination of the active ingredient with a suitable base material contain. Suitable basic materials are, for example, liquid triglycerides, Polyethylene glycols or paraffin hydrocarbons.
Für eine parenterale Verabreichung eignen sich insbesondere wässrige Lösungen eines Wirkstoffs in wasserlöslicher Form, beispielsweise in Form eines wasserlöslichen Salzes, und auch Suspensionen des Wirkstoffs, wie entsprechende ölige Injektionssuspensionen, wobei geeignete lipophile Lösemittel oder Träger verwendet werden, wie Fettöle, beispielsweise Sesamöl, oder synthetische Fettsäweester, beispielsweise Ethyloleat oder Triglyceride, oder wässrige Injektionssuspensionen, die viskositätserhöhende Substanzen enthalten, beispielsweise Natnumcarboxymethylcellulose, Sorbit und/oder Dextran, und optional auch Stabilisatoren.For a parenteral Administration are particularly suitable aqueous solutions of an active ingredient in water-soluble Form, for example in the form of a water-soluble salt, and also suspensions of the active substance, such as corresponding oily injection suspensions, wherein suitable lipophilic solvents or carrier used be like fatty oils, for example sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, or aqueous injection suspensions, the viscosity-increasing substances For example, Natnumcarboxymethylcellulose, sorbitol and / or Dextran, and optionally stabilizers.
Die Dosis des Wirkstoffs ist abhängig von der Art des Warmblüters, dem Alter und dem individuellen Zustand und auch der Art der Verabreichung. In Normalfall reicht die ungefähre Tagesdosis für eine orale Verabreichung an einen Patienten mit einem Körpergewicht von etwa 75 kg von etwa 10 mg bis etwa 500 mg.The Dose of the drug is dependent of the type of warm-blooded animal, the age and individual condition and also the mode of administration. Normally, the approximate range Daily dose for oral administration to a patient of body weight from about 75 kg from about 10 mg to about 500 mg.
Durch die folgenden Beispiele wird die Erfindung weiter erläutert, wobei alle Temperaturen in °C und alle Drücke in mbar angegeben sind.By the following examples, the invention is further explained, wherein all temperatures in ° C and all the pressures are given in mbar.
Beispiel 1: N-(2,3-Dioxo-7-nitro-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)2-methylaziridinhydrobromidExample 1: N- (2,3-Dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) 2-methylaziridine hydrobromide
Man rührt 180 mg (0,59 mmol) N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)-2-methylaziridin in einer 33%igen Lösung von Bromwasserstoff in Essigsäwe während 2 h bei 70°C. Das Gemisch wird dann mit Diethylether verdünnt, worauf der Feststoff abfiltriert und mit Diethylether gewaschen wird.you stirs 180 mg (0.59 mmol) N- (2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl) -2-methylaziridine in a 33% solution of hydrogen bromide in acetic acid while 2 h at 70 ° C. The mixture is then diluted with diethyl ether, whereupon the solid is filtered off and washed with diethyl ether.
Nach Trocknung ergibt sich die Titelverbindung in Form eines gelben Feststoffs. Smp. = 241°C (Zersetzung) Das Ausgangsmaterial kann beispielsweise wie folgt hergestellt werden:To Drying gives the title compound as a yellow solid. Mp = 241 ° C (Decomposition) The starting material may be, for example, as follows getting produced:
- a) N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)2-methylaziridin Man rührt 200 mg (0,61 mmol) 5-Brommethyl-2,3-dimethoxy-7-nitrochinoxalin, 0,086 ml (2 Äquivalente) Propylemin und 0,295 ml (0,3 Äquivalente) einer wässrigen 40%igen Lösung von Tetrabutylammoniumhydroxid in 8 ml Dichlormethan während 20 h bei Raumtemperatur. Das Gemisch wird dann durch Verdampfen eingeengt und der Rückstand hierauf mit Ethylacetat und einer 5%igen Natriumcarbonatlösung extrahiert. Die vereinigten organischen Phasen werden einmal mit Kochsalzlösung gewaschen, über Magnesiumsulfat getrocknet und durch Verdampfung eingeengt.a) N- (2,3-Dimethoxy-7-nitroquinoxalin-5-ylmethyl) 2-methylaziridine Man stirs 200 mg (0.61 mmol) 5-bromomethyl-2,3-dimethoxy-7-nitroquinoxaline, 0.086 ml (2 equivalents) Propylemin and 0.295 ml (0.3 equivalents) an aqueous 40% solution of tetrabutylammonium hydroxide in 8 ml of dichloromethane for 20 h at room temperature. The mixture is then concentrated by evaporation and the residue then extracted with ethyl acetate and a 5% sodium carbonate solution. The combined organic phases are washed once with brine, over magnesium sulfate dried and concentrated by evaporation.
1H-NMR (CDCl3, 250 MHz): 8,6 (m,2H), 4,18 (m, 2Me+H), 3,95 (s, 2H), 3,38 (m, 2H), 1,0 (6,Me). 1 H-NMR (CDCl 3, 250 MHz): 8.6 (m, 2H), 4.18 (m, 2Me + H), 3.95 (s, 2H), 3.38 (m, 2H), 1.0 (6, Me).
Beispiel 2: cis-2-[N-(7-Nitro-2,3-dioxo-1,2,3,4tetrahydrochinoxalin-5-ylmethyl)amino]cyclohexan-1-carbonsäurehydrobromidExample 2: Cis-2- [N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -amino] cyclohexane-1-carboxylic acid hydrobromide
Die Titelverbindung kann wie im Beispiel 1 beschrieben hergestellt werden, jedoch ausgehend von cis-2-[N(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)amino]cyclohexan-l-cartionsäwe anstelle von N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)-2-metliylaziridin.The Title compound can be prepared as described in Example 1, however, starting from cis-2- [N (2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl) amino] cyclohexane-1-cartionic acid instead of N- (2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl) -2-methylthiazole.
Smp. = 249 bis 251 °C; ESCIMS: (M-H)+ = 361; TLC: Methanol/Essigsäure (9:1) R1 = 0,1 bis 0,45. Das Ausgangsmaterial kann beispielsweise wie folgt hergestellt werden:Mp = 249 to 251 ° C; ESCIMS: (MH) + = 361; TLC: methanol / acetic acid (9: 1) R 1 = 0.1 to 0.45. The starting material can be prepared, for example, as follows:
- a) 2,3-Dimethoxychinoxalin-5-carbaldehyda) 2,3-Dimethoxyquinoxaline-5-carbaldehyde
- Man gibt 17 ml (188 mmol) 2-Nitropropan zu einer Lösung von 3,7 g (163 mmol) Natrium in 700 ml Methanol. Nach 5 min langem Rühren werden 35,5 g (125,4 mmol) festes 2,3-Dime[hoxy-5-brommethylchinoxalin zugesetzt. Das Gemisch wird 1 h auf Rückflusstemperatur gehalten, wodurch eine homogene Lösung entsteht. Nach Abkühlung wird diese Lösung unter verringertem Druck eingeengt. Der Rückstand wird in Ethylacetat und 1 n HCl aufgenommen und die Phasen werden voneinander getrennt, worauf die organische Phase mit Wasser und Kochsalzlösung gewaschen, über Natriumsulfat getrocknet und eingeengt wird. Die Titelverbindung wird in Form weißer Kristalle durch Kristallisation aus Ethylacetat isoliert. Smp. = 137 bis 140°C; TLC (EtOAc/Hexan 1:3): Rf= 0,45.Add 17 ml (188 mmol) of 2-nitropropane to a solution of 3.7 g (163 mmol) of sodium in 700 ml of methanol. After stirring for 5 minutes 35.5 g (125.4 mmol) of solid 2,3-dime [hoxy-5-bromomethylquinoxaline added. The mixture is at reflux temperature for 1 h held, creating a homogeneous solution. After cooling it will this solution concentrated under reduced pressure. The residue is taken up in ethyl acetate and 1 n HCl are added and the phases are separated from each other, after which the organic phase is washed with water and brine, over sodium sulfate is dried and concentrated. The title compound is in shape white Crystals isolated by crystallization from ethyl acetate. M = 137 to 140 ° C; TLC (EtOAc / hexane 1: 3): Rf = 0.45.
- b) 2,3-Dimethoxy-7-nitrochinoxalin-5-carbaldehyd Man gibt 44 ml 100%iger Salpetersäwe, 44 ml 97%iger Schwefelsäure und 44 ml Trifluoressigsäureanhydrid der Reihe nach zu einer auf 0°C gekühlten Lösung von 22 g (100,8 mmol) 2,3-Dimethoxy-5-brommethylchinoxalin in 88 ml Trifluoressigsäure. Das Gemisch wird 2 h auf 0°C gehalten und dann vorsichtig auf ein Gemisch aus 4 n NaOH und Eis gegossen. Hierbei sollte die Temperatur nicht über 20°C hinausgehen. Das erhaltene Gemisch wird dann mit Ethylacetat extrahiert. Die organische Phase wird mit einer wässrigen 1 n NaOH Lösung, Wasser und Kochsalzlösung gewaschen und über Natriumsulfat getrocknet. Durch Kristallisation des Rohprodukts ergibt sich die Titelverbindung in Form hellgelber Kristalle. Smp. = 147 bis 149°C; TLC (EtOAc/Hexan 1:3): Rf= 0,25.b) 2,3-Dimethoxy-7-nitroquinoxaline-5-carbaldehyde There are 44 100% nitric acid, 44 ml of 97% sulfuric acid and 44 ml of trifluoroacetic anhydride in turn to 0 ° C cooled Solution of 22 g (100.8 mmol) of 2,3-dimethoxy-5-bromomethylquinoxaline in 88 ml of trifluoroacetic acid. The Mixture is at 0 ° C for 2 h and then carefully onto a mixture of 4N NaOH and ice cast. The temperature should not exceed 20 ° C. The obtained Mixture is then extracted with ethyl acetate. The organic phase comes with an aqueous 1N NaOH solution, Washed water and brine and over Dried sodium sulfate. By crystallization of the crude product the title compound results in the form of pale yellow crystals. Mp. = 147 to 149 ° C; TLC (EtOAc / hexane 1: 3): Rf = 0.25.
- e) cis-2-[N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)amino]cyclohexan-l-carbonsäure Man gibt 105 mg (0,588 mmol) cis-2-Aminocyclohexancarbonsäure und 82 µl(0,588 mmol) Triethylamin der Reihe nach zu einer Lösung von 129 mg (0,490 mmol) 2,3-Dimethoxy-7-nitrochinoxanlin-5-carbaldehyd in 1 ml Dichlormethan und 2 ml Ethanol. Nach 3 h langem Rühren bei Raumtemperatur wird die Suspension mir 1 g wasserfreiem Natriumsulfat versetzt und das Gemisch weitere 20 h bei Raumtemperatur gerührt. Die erhaltene dicke Suspension wird mit 0,5 ml Ethanol und 46 mg (1,23 mmol) Nartriumborhydrid versetzt. Nach 3 h langem Rühren werden zunächst 0,5 ml Aceton und 10 min später 0,3 ml Essigsäure zugegeben, worauf filtriert wird. Der Filterrückstand wird mit Ethanol und Dichlormethan gewaschen. Das Filtrat wird über Silicagel chromatographiert, und zwar zuerst mit Dichlormethan/Ethylacetat (97:3) und dann mit Dichlormethan/Methanol/Eisessig (90:9:1). Die Titelverbindung wird in Form eines weißen Pulvers erhalten.e) cis-2- [N- (2,3-Dimethoxy-7-nitroquinoxalin-5-ylmethyl) amino] cyclohexane-1-carboxylic acid Man gives 105 mg (0.588 mmol) of cis-2-aminocyclohexanecarboxylic acid and 82 μl (0.588 mmol) triethylamine in order to a solution of 129 mg (0.490 mmol) 2,3-Dimethoxy-7-nitroquinoxanine-5-carbaldehyde in 1 ml of dichloromethane and 2 ml of ethanol. After 3 hours of stirring at room temperature the suspension is mixed with 1 g of anhydrous sodium sulfate and the Mixture stirred for a further 20 h at room temperature. The resulting thick suspension is treated with 0.5 ml of ethanol and 46 mg (1.23 mmol) of sodium borohydride added. After 3 h stirring be first 0.5 ml of acetone and 10 minutes later 0.3 ml of acetic acid added, whereupon filtered. The filter residue is mixed with ethanol and Washed dichloromethane. The filtrate is chromatographed on silica gel, first with dichloromethane / ethyl acetate (97: 3) and then with Dichloromethane / methanol / glacial acetic acid (90: 9: 1). The title link will in the form of a white one Obtained powder.
Beispiel 3:Example 3:
In
analoger Weise zur Beschreibung des Beispiels 2 werden auch die
folgenden Verbindungen hergestellt:
N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)aminomethanphosphonsäurehydrobromid;
N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)amino-(3-methoxyphenyl)methanphosphonsäurehydrochlond,
FAB-MS: M+ = 436; HPLC: CH3CN/H2O
+ 0,1 % Trifluoressigsäure
20:80 R1 = 4,2 min. (Nucleosil1 00.
C18, 5 µM,
250 × 4,6
mm);
[(7-Nitro-2,3-dioxo- 1,2,3,4-tetrahydrochinoxalin-5-yl-methylamino)-(3-hydroxyphenyl)-methyl]phosphonsäurehydrobromid,
FAB-MS: M+ = 422; HPLC: CH3CN/H2O
+ 0,1 % Trifluoressigsäure
20:80 R1 = 2,9 min. (Nucleosil100,
C18, 5 µM,
250 × 4,6
mm);
N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-3-aminopropan-1-phosphonsäurehydrobromid; trans-2-[N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)amino]cyclopropan-1-phosphonsäwehydrobromid;
N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yhnethyl)amino-(3-pyridyl)methanphosphonsäwehydrochlorid;
N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yhnethyl)-3-amino-l-carboxypropan-lphosphonsäurehydrobromid.In an analogous manner to the description of Example 2, the following compounds are herge provides:
N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) aminomethanphosphonsäurehydrobromid;
N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino- (3-methoxyphenyl) methanephosphonic acid hydrochloride, FAB-MS: M + = 436; HPLC: CH 3 CN / H 2 O + 0.1% trifluoroacetic acid 20:80 R 1 = 4.2 min. (Nucleosil 1 00.C 1 8, 5 μM, 250 x 4.6 mm);
[(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl-methylamino) - (3-hydroxyphenyl) -methyl] -phosphonic acid hydrobromide, FAB-MS: M + = 422; HPLC: CH 3 CN / H 2 O + 0.1% trifluoroacetic acid 20:80 R 1 = 2.9 min. (Nucleosil 1 00, C 1 8, 5 uM, 250 x 4.6 mm);
N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -3-aminopropane-1-phosphonsäurehydrobromid; trans-2- [N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino] cyclopropane-1-phosphonsäwehydrobromid;
N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) amino (3-pyridyl) methanphosphonsäwehydrochlorid;
N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -3-amino-l-carboxypropane-lphosphonsäurehydrobromid.
Beispiel 4: N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmetliyl)2-aminethanphosphonsäurehydrobromidExample 4: N- (7-Nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl-methyl) 2-aminoethane phosphonic acid hydrobromide
Man löst 380 mg (0,949 mmol) N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)2-aminoethanphosphonsäuredimethylester und 1,23 ml (10 Äquivalente) Trimethylsilylbromid in 20 ml Dichlormethane und rührt die Lösung dann 90 min bei Raumtemperatur. Das Reaktionsgemisch wird durch Verdampfung eingeengt und der Rückstand 17 h bei 40°C in 6 ml einer etwa 33%igen Lösung von Bromwasserstoff in Essigsäwe gerührt. Das Reaktionsgemisch wird mit Diethylether verdünnt, worauf der Feststoff abfiltriert, gründlich mit Diethylether gewaschen und dann getrocknet wird. Hierdurch ergibt sich die Titelverbindung in Form eines gelblichen Feststoffs.you triggers 380 mg (0.949 mmol) of N- (2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl) 2-aminoethane-phosphonic acid dimethyl ester and 1.23 ml (10 equivalents) Trimethylsilylbromid in 20 ml of dichloromethane and stir the solution then 90 minutes at room temperature. The reaction mixture is through Evaporation concentrated and the residue 17 h at 40 ° C in 6 ml of an approximately 33% solution of hydrogen bromide in acetic acid touched. The Reaction mixture is diluted with diethyl ether, whereupon the solid is filtered off, thoroughly washed with diethyl ether and then dried. This results the title compound in the form of a yellowish solid.
Smp. = 235°C (Zersetzung).Mp. = 235 ° C (Decomposition).
Die Ausgangsmaterialien lassen sich beispielsweise wie folgt herstellen:The Starting materials can be prepared, for example, as follows:
- a) N-(2,3-Dimethoxy-7-nitrochinoxalin-5-ylmethyl)-2-aminoethanprtosphonsäuredimethylestera) N- (2,3-dimethoxy-7-nitroquinoxalin-5-ylmethyl) -2-aminoethane-prtosphonate
- Man löst 0,19 ml (1,2 Äquivalente) Methylamin, 0,215 ml(1,5 Äquivalente) Trimethylchlorsilan und 0,104 ml Dimethylphosphit in Dichlormethan bei 0°C und rührt die Lösung während 20 min. Das erhaltene Reaktionsgemisch wird mit einer Lösung von 329 mg (1,135 mmol) 2,3-Dimethoxy-5-ethylidenaminomethyl-7-nitrochinoxalin in Dichlormethan versetzt und zuerst während 5 h bei 0°C und dann 12 h bei Raumtemperatur gerührt. Die Lösung wird mit Wasser verdünnt und dreimal mit Dichlormethan extrahiert. Die organische Phase wird vereinigt, über Magnesiumsulfat getrocknet und durch Verdampfung eingeengt. Die Titelverbindung wird in Form eines gelben Feststoffs erhalten.Man dissolves 0.19 ml (1.2 equivalents) Methylamine, 0.215 ml (1.5 equivalents) Trimethylchlorosilane and 0.104 ml of dimethyl phosphite in dichloromethane at 0 ° C and stir the solution while 20 min. The resulting reaction mixture is washed with a solution of 329 mg (1.135 mmol) of 2,3-dimethoxy-5-ethylideneaminomethyl-7-nitroquinoxaline in dichloromethane and first for 5 h at 0 ° C and then Stirred for 12 h at room temperature. The solution is diluted with water and extracted three times with dichloromethane. The organic phase becomes united, over Dried magnesium sulfate and concentrated by evaporation. The Title compound is obtained in the form of a yellow solid.
- b) 2,3-Dimethoxy-5-ethvlidenaminomethyl-7-nitrochinoxalinb) 2,3-dimethoxy-5-ethidylaminomethyl-7-nitroquinoxaline
- Man suspendiert 300 mg (1,135 mmol) 2,3-Dimethoxy-5-aminomethyl-7-nitrochinoxaline, 500 mg (3,7 Äquivalente) Magnesiumsulfat und 200 mg (1,28 Äquivalente) Kaliumcarbonat in 20 ml Dichlormethan bei Raumtemperatur. Nach 15 min gibt man 0,13 ml Acetaldehyd zu und rührt das Reaktionsgemisch 7 h bei Raumtemperatur, worauf es filtriert und durch Verdampfung eingeengt wird.300 mg (1.135 mmol) of 2,3-dimethoxy-5-aminomethyl-7-nitroquinoxaline are suspended, 500 mg (3.7 equivalents) Magnesium sulfate and 200 mg (1.28 equiv.) Of potassium carbonate in 20 ml of dichloromethane at room temperature. After 15 minutes you give 0.13 ml of acetaldehyde and stirred the reaction mixture for 7 h at room temperature, whereupon it is filtered and concentrated by evaporation.
Beispiel 5Example 5
In analoger Weise zur Beschreibung der Beispiele 2 bis 4 können auch die folgenden Verbindungen herge stellt werden:In analogous to the description of Examples 2 to 4 can also the following compounds are manufactured:
- N-(2,3-Dioxo-7-nitro- 1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-4-amino-n-butylphosphonsäurehydrobromid, MS(ES+): (M+H)+ = 373,N- (2,3-dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -4-amino-n-butylphosphonic acid hydrobromide, MS (ES +): (M + H) + = 373,
- N-(2,3-Dioxo-7-nitro- 1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-N-methyl)-4-amino-n-butylphosphonsäurehydrobromid, MS(ES+): (M+H)+ = 387;N- (2,3-dioxo-7-nitro-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -N-methyl) -4-amino-n-butylphosphonic acid hydrobromide, MS (ES +): (M + H) + = 387;
- 1-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yhnethylamino)ethanphosphonsäure;1- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yhnethylamino) ethanephosphonic acid;
- N-(7-Nitro-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yl)-carbamoylmethanphosphonsäure;N- (7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl) -carbamoylmethanphosphonsäure;
- 7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethylaminomethanphosphonsäure, Smp >270°C;7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-ylmethylaminomethanephosphonic acid, mp> 270 ° C;
- 1-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-yhnethylamino)ethanphosphonsäue;1- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yhnethylamino) ethanphosphonsäue;
- N-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl-N-benzyloxycarbonylaminomethanphosphonsäure;N- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl-N-benzyloxycarbonylaminomethanphosphonsäure;
- N-(7-Brom-2,3-dioxo-1,2,3,4-tetrahydrochinoxalin-5-ylmethyl)-N-phenylacetylaminomethanphosphonsäure.N- (7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethyl) -N-phenylacetylaminomethanphosphonsäure.
Beispiel 6: Tabletten mit einem Wirkstoffgehalt von jeweils 50 mg lassen sich wie folgt herstellenExample 6: Tablets with an active ingredient content of 50 mg each can be prepared as follows
) Zusammensetzung
(10 000 Tabletten
Der Wirkstoff wird mit der Lactose und mit 292 g Kartoffelstärke vermischt, worauf das Gemisch mit einer ethanolischen Lösung der Gelatine befeuchtet und durch ein Sieb granuliert wird. Nach Trocknung wird der Rest der Kartoffelstärke, das Magnesiumstearat, das Talcum und das Siliciumdioxid eingemischt und das Gemisch unter Bildung von Tabletten verpresst, die jeweils 145 mg wiegen und 50,0 mg Wirkstoff enthalten. Die Tabletten können zur feineren Anpassung der Dosis gewünschtenfalls mit Brechkerben versehen werden.Of the Active ingredient is mixed with the lactose and with 292 g potato starch, whereupon the mixture moistened with an ethanolic solution of gelatin and granulated through a sieve. After drying, the rest the potato starch, the magnesium stearate, talcum and silica mixed and compressing the mixture to form tablets, each Weigh 145 mg and contain 50.0 mg of active ingredient. The tablets can be used for fine adjustment of the dose if desired be provided with breaking notches.
Beispiel 7Example 7
Eine
steril filtrierte wässrige
Gelatinelösung,
die 20% Cyclodextrine als Lösungsvermittler
und 3 mg einer Verbindung nach einem der Beispiele 3 bis 5 als Wirkstoff
enthält,
wird unter aseptischen Bedingungen und Erhitzung mit einer sterilen
Gelatinelösung
vermischt, die Phenol als Konservierungsmittel in einer Menge enthält, das
eine Lösung
von 1,0 ml die folgende Zusammensetzung aufweist:
Beispiel 8Example 8
Zur Herstellung einer sterilen Trockensubstanz zur Injektion löst man 5 mg einer der in den vorherigen Beispielen beschriebenen Verbindungen der Formel I als Wirkstoff in 1 ml einer wässrigen Lösung, die 20 mg Mannit und 20% Cyclodextrine als Lösungsvermittler enthält. Die Lösung wird steril filtriet und unter aseptischen Bedingungen in eine 2 mlAmpulle gegeben, tiefgefroren und lyophilisiert. Vor einer Anwendung wird das Lyophilisat in 1 ml destilliertem Wasser oder in 1 ml einer physiologischen Kochsalzlösung gelöst. Die Lösung wird intramuskulär oder intravenös verabreicht. Diese Formulierung kann auch in Doppelkammerinjektionsampullen gegeben werden.to Preparation of a sterile dry substance for injection is dissolved 5 mg of one of the compounds described in the previous examples of formula I as active ingredient in 1 ml of an aqueous solution containing 20 mg of mannitol and 20% cyclodextrins as solubilizers contains. The solution is sterile filtered and placed under aseptic conditions in a 2 ml of ampoule, frozen and lyophilized. Before an application The lyophilisate is dissolved in 1 ml of distilled water or in 1 ml of a physiological saline solved. The solution will be intramuscularly or intravenously administered. This formulation can also be used in dual-chamber injection vials are given.
Beispiel 9Example 9
In
folgender Weise können
auch 10 000 filmbeschichtete Tabletten hergestellt werden, die jeweils
100 mg einer Verbindung nach einem der Beispiele 2 bis 5 enthalten.
Man verarbeitet ein Gemisch aus einer der in den vorherigen Beispielen erwähnten Verbindungen der Formel I als Wirkstoff, 50 g Maisstärke und der kolloidalen Kieselsäure mit einer Stärkepaste, die aus 250 g Maisstärke und 2,2 kg demineralisiertem Wasser besteht, unter Bildung einer feuchten Masse. Die erhaltene feuchte Masse wird durch ein Sieb mit einer Maschengröße von 3 mm gepresst und 30 min bei 45°C in einem Fließbetttrockner getrocknet. Die getrockneten Granulate werden durch ein Sieb mit einer Maschengröße von 1 mm gepresst, mit einem vorher gesiebten Gemisch (Siebgröße 1 mm) aus 330 g Maisstärke, dem Magnesiumstearat, der Stearinsäure und der Natriumcarboxymethylstärke vermischt und unter Bildung leicht biconvexer Tabletten verpprsst.A mixture of one of the compounds of formula I mentioned in the previous examples as active ingredient, 50 g of corn starch and the colloidal silica with a starch paste consisting of 250 g Corn starch and 2.2 kg of demineralized water to form a wet mass. The resulting wet mass is forced through a sieve with a mesh size of 3 mm and dried for 30 min at 45 ° C in a fluid bed dryer. The dried granules are squeezed through a sieve of mesh size 1 mm, mixed with a previously sieved mixture (sieve size 1 mm) from 330 g of corn starch, magnesium stearate, stearic acid and sodium carboxymethyl starch and compressed to form slightly biconvex tablets.
Claims (2)
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
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CH247995 | 1995-08-31 | ||
CH247995 | 1995-08-31 | ||
CH273495 | 1995-09-27 | ||
CH273495 | 1995-09-27 | ||
CH274795 | 1995-09-28 | ||
CH274795 | 1995-09-28 | ||
CH121396 | 1996-05-10 | ||
CH121396 | 1996-05-10 | ||
CH163096 | 1996-06-28 | ||
CH163096 | 1996-06-28 | ||
PCT/EP1996/003644 WO1997008155A1 (en) | 1995-08-31 | 1996-08-19 | Novel 2,3-dioxo-1,2,3,4-tetrahydro-quinoyxalinyl derivatives |
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Publication Number | Publication Date |
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DE69631774D1 DE69631774D1 (en) | 2004-04-08 |
DE69631774T2 true DE69631774T2 (en) | 2005-01-13 |
Family
ID=27508939
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DE69631774T Expired - Lifetime DE69631774T2 (en) | 1995-08-31 | 1996-08-19 | 2,3-DIOXO-1,2,3,4-TETRAHYDRO-CHINOXALINE DERIVATIVES |
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EP (1) | EP0853617B1 (en) |
JP (1) | JP3159711B2 (en) |
KR (1) | KR100462337B1 (en) |
CN (1) | CN1137886C (en) |
AR (1) | AR005229A1 (en) |
AT (1) | ATE260902T1 (en) |
AU (1) | AU705871B2 (en) |
BR (1) | BRPI9603626B8 (en) |
CA (1) | CA2227851C (en) |
CZ (1) | CZ56298A3 (en) |
DE (1) | DE69631774T2 (en) |
DK (1) | DK0853617T3 (en) |
ES (1) | ES2217324T3 (en) |
HK (1) | HK1010196A1 (en) |
HU (1) | HUP9801676A3 (en) |
IL (1) | IL122987A (en) |
MY (1) | MY132385A (en) |
NO (1) | NO310236B1 (en) |
NZ (1) | NZ316497A (en) |
PL (1) | PL189637B1 (en) |
PT (1) | PT853617E (en) |
SI (1) | SI0853617T1 (en) |
SK (1) | SK25298A3 (en) |
TR (1) | TR199800349T2 (en) |
WO (1) | WO1997008155A1 (en) |
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---|---|---|---|---|
US6191134B1 (en) * | 1996-06-05 | 2001-02-20 | Warner-Lambert Company | Amide derivatives of substituted quinoxaline 2, 3-diones as glutamate receptor antagonists |
WO1998017672A1 (en) * | 1996-10-24 | 1998-04-30 | Novartis Ag | Substituted aminoalkane phosphonic acids |
ZA9710553B (en) * | 1996-11-25 | 1998-06-10 | Warner Lambert Co | Urea and thiourea derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists. |
GB9702194D0 (en) | 1997-02-04 | 1997-03-26 | Lilly Co Eli | Sulphonide derivatives |
US6172065B1 (en) * | 1997-03-04 | 2001-01-09 | Warner-Lambert Company | Urea and thiourea derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists |
US6340758B1 (en) | 1997-05-16 | 2002-01-22 | Warner-Lambert Company | Conformationally semi-constrained quinoxaline 2,3-diones as neuroprotective agents |
US6096744A (en) * | 1998-05-04 | 2000-08-01 | Warner-Lambert Company | Sulfonamide derivatives of substituted quinoxaline 2,3-diones as glutamate receptor antagonists |
US6635661B2 (en) | 2000-05-25 | 2003-10-21 | Sepracor Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US6677332B1 (en) | 1999-05-25 | 2004-01-13 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
US7361666B2 (en) | 1999-05-25 | 2008-04-22 | Sepracor, Inc. | Heterocyclic analgesic compounds and methods of use thereof |
WO2001092226A1 (en) * | 2000-05-25 | 2001-12-06 | Sepracor, Inc. | Heterocyclic analgesic compounds and method of use thereof |
WO2002072542A2 (en) * | 2001-03-08 | 2002-09-19 | Emory University | Ph-dependent nmda receptor antagonists |
TW200403066A (en) * | 2002-04-30 | 2004-03-01 | Novartis Ag | New uses of substituted aminoalkanephosphonic acids |
GB0310868D0 (en) * | 2003-05-12 | 2003-06-18 | Novartis Ag | Organic compounds |
WO2004101533A1 (en) * | 2003-05-12 | 2004-11-25 | Janssen Pharmaceutica, N.V. | 1, 3, 4-benzotriazepin-2-one salts and their use as cck receptor ligands |
MXPA06003578A (en) * | 2003-09-30 | 2006-08-31 | Johnson & Johnson | Quinoxaline compounds. |
US20060020029A1 (en) * | 2004-07-02 | 2006-01-26 | Shimasaki Craig D | Pharmaceutical compositions from ethnobotanicals |
UA95788C2 (en) * | 2005-12-15 | 2011-09-12 | Ф. Хоффманн-Ля Рош Аг | Fused pyrrole derivatives |
NZ582917A (en) | 2007-06-29 | 2013-01-25 | Univ Emory | Nmda receptor antagonists for neuroprotection |
US20130053381A1 (en) * | 2010-05-20 | 2013-02-28 | Novartis Ag | 2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl-sulfonamide derivatives |
US9737531B2 (en) | 2012-07-12 | 2017-08-22 | Glytech, Llc | Composition and method for treatment of depression and psychosis in humans |
JO3225B1 (en) * | 2012-11-27 | 2018-03-08 | Lilly Co Eli | 6-((s)-1-{1-[5-(2-hydroxy-ethoxy)-pyridin-2-yl]-1h-pyrazol-3-yl}-ethyl)-3h-1,3-benzothiazol-2-one as a tarp-gamma 8 dependent ampa receptor antagonist |
CN103435561B (en) * | 2013-08-19 | 2016-08-10 | 上海交通大学 | A kind of Novel D-amino acid oxidase inhibitor and preparation thereof and application |
SG11201906803WA (en) * | 2017-01-27 | 2019-08-27 | Genfit | N-{[2-(piperidin-1-yl)phenyl](phenyl)methyl}-2-(3-oxo-3,4-dihydro-2h-1,4-benzoxa zin-7-yl)acetamide derivatives and related compounds as ror-gamma modulators for treating autoimmune diseases |
MX2019015120A (en) | 2017-06-12 | 2022-07-14 | Glytech Llc | Treatment of depression with nmda antagonists and d2/5ht2a or selective 5ht2a antagonists. |
Family Cites Families (6)
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US4156734A (en) * | 1976-02-13 | 1979-05-29 | Merck & Co., Inc. | Antihypertensive compositions containing an aryl-substituted alanine azo and an arylhydrazino-propionic acid |
CA2002864C (en) * | 1988-11-29 | 1999-11-16 | Eddy J. E. Freyne | (1h-azol-1-ylmethyl) substituted quinoline, quinazoline or quinoxaline derivatives |
JPH04506967A (en) * | 1989-07-27 | 1992-12-03 | ジー.ディー.サール アンド カンパニー | Renal selective products for the treatment of hypertension |
US5631373A (en) * | 1993-11-05 | 1997-05-20 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon | Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones |
GB9418443D0 (en) * | 1994-09-13 | 1994-11-02 | Pfizer Ltd | Therapeutic agents |
GB9419318D0 (en) * | 1994-09-24 | 1994-11-09 | Pfizer Ltd | Therapeutic agents |
-
1996
- 1996-08-12 MY MYPI96003300A patent/MY132385A/en unknown
- 1996-08-19 JP JP50980197A patent/JP3159711B2/en not_active Expired - Fee Related
- 1996-08-19 ES ES96929275T patent/ES2217324T3/en not_active Expired - Lifetime
- 1996-08-19 DK DK96929275T patent/DK0853617T3/en active
- 1996-08-19 HU HU9801676A patent/HUP9801676A3/en unknown
- 1996-08-19 PT PT96929275T patent/PT853617E/en unknown
- 1996-08-19 KR KR10-1998-0701511A patent/KR100462337B1/en not_active IP Right Cessation
- 1996-08-19 SK SK252-98A patent/SK25298A3/en unknown
- 1996-08-19 PL PL96324992A patent/PL189637B1/en not_active IP Right Cessation
- 1996-08-19 WO PCT/EP1996/003644 patent/WO1997008155A1/en not_active Application Discontinuation
- 1996-08-19 IL IL12298796A patent/IL122987A/en not_active IP Right Cessation
- 1996-08-19 NZ NZ316497A patent/NZ316497A/en unknown
- 1996-08-19 DE DE69631774T patent/DE69631774T2/en not_active Expired - Lifetime
- 1996-08-19 TR TR1998/00349T patent/TR199800349T2/en unknown
- 1996-08-19 CZ CZ98562A patent/CZ56298A3/en unknown
- 1996-08-19 EP EP96929275A patent/EP0853617B1/en not_active Expired - Lifetime
- 1996-08-19 CA CA002227851A patent/CA2227851C/en not_active Expired - Fee Related
- 1996-08-19 AT AT96929275T patent/ATE260902T1/en active
- 1996-08-19 CN CNB961965819A patent/CN1137886C/en not_active Expired - Fee Related
- 1996-08-19 AU AU68742/96A patent/AU705871B2/en not_active Ceased
- 1996-08-19 SI SI9630678T patent/SI0853617T1/en unknown
- 1996-08-19 US US09/029,525 patent/US6080743A/en not_active Expired - Lifetime
- 1996-08-30 BR BRPI9603626A patent/BRPI9603626B8/en not_active IP Right Cessation
- 1996-08-30 AR ARP960104160A patent/AR005229A1/en active IP Right Grant
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1998
- 1998-02-26 NO NO19980814A patent/NO310236B1/en unknown
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8364 | No opposition during term of opposition | ||
8328 | Change in the person/name/address of the agent |
Representative=s name: KROHER, STROBEL RECHTS- UND PATENTANWAELTE, 80336 |
|
8328 | Change in the person/name/address of the agent |
Representative=s name: DR. SCHOEN & PARTNER, 80336 MUENCHEN |